'Spark of Hope' for Tau Inhibitor in
Alzheimer's Disease

Megan Brooks

December 06, 2019

New data on the experimental tau inhibitor hydromethylthionine (TauRx Ltd) has turned up some unexpected results in a post-hoc analysis, according to its manufacturer.

Even at the "control" dose of 8 mg per day, the drug produced concentration-dependent effects on cognitive decline and brain atrophy when used alone or added to symptomatic treatment in patients with mild to moderate Alzheimer's disease (AD).

The results are "striking," Claude Wischik, MD, PhD, executive chairman of TauRx Therapeutics and professor of psychiatric gerontology at the University of Aberdeen, United Kingdom, told Medscape Medical News.

"The 8 mg/day dose was used previously in the completed phase 3 trials merely to mask urinary discoloration, thinking it would not have pharmacological activity," Wischik said.

The findings were published online November 26 in the Journal of Alzheimer's Disease.

Large Cognitive Effects

Hydromethylthionine is a potent tau aggregation inhibitor. In two phase 3 clinical trials conducted in nearly 1700 patients with mild-to-moderate AD, the drug was tested at doses of 150 to 250 mg per day against the 8 mg per day "control" dose.

Surprisingly, there was no significant difference between the high doses and the low dose of hydromethylthionine on any of the clinical outcomes.

To further explore these results, the investigators conducted an exploratory post hoc pharmacokinetic analysis to determine the extent to which drug exposure determines treatment response on clinical and MRI volumetric endpoints. They included 1162 patients who participated in the phase 3 trials.

Using a sensitive plasma assay, the researchers found that most patients had high enough plasma concentrations at the 8 mg/day dose (range, 0.3 – 0.8 ng/mL) to produce meaningful reductions in cognitive decline and brain atrophy. Higher plasma concentrations in the range of 4 to 21 ng/mL produced by the high doses were not associated with any additional benefit.

"Most patients achieve pharmacological activity already at the 8 mg/day dose and this reaches a plateau above a predicted dose of 16 mg/day," Wischik said. "This explains the lack of dose-response seen in the phase 3 trials comparing 8 mg/day with 150 to 250 mg/day."

In addition to the reduction in brain atrophy, "we were surprised to see the large cognitive effects of treatment in the patient group with the higher blood levels of hydromethylthionine at the 8 mg daily dose,” Wischik said in a news release.

According to scores on the 11-item AD Assessment Scale-cognitive subscale, "the effect was around 7.5 points, or three times that seen from current routine Alzheimer's treatments, and would be equivalent to an 85% reduction in cognitive decline over 65 weeks," he added.

The new analysis also shows that hydromethylthionine has similar exposure-response profiles both as an add-on to standard symptomatic treatments and as monotherapy — but with activity reduced by about half as add-on compared with monotherapy.

This finding supports the hypothesis that symptomatic drugs for AD interfere with the disease-modifying treatment effects of hydromethylthionine.

"Best Hope We Have Right Now"

There is already a substantial database supporting the safety and tolerability of hydromethylthionine in clinical trials of patients with mild-to-moderate AD, Wischik noted. 

The results from this new analysis have "given us the confidence to expand the scope of the new TauRx LUCIDITY clinical trial to confirm the potential efficacy of the hydromethylthionine 16 mg/day dose in these types of patients," he added.

"Hydromethylthionine looks to have the most promising profile of any drug currently in late-stage development," Wischik told Medscape Medical News.

In the news release, George Perry, PhD, editor-in-chief of the Journal of Alzheimer's Disease, commented that "the extensive data, experience, and now pharmacokinetics highlight the potential of hydromethylthionine treatment as an important new avenue forward in Alzheimer's disease. The clinical benefit and reduction in brain atrophy greatly exceed those reported for other therapeutic routes.”

Coinvestigator Serge Gauthier, MD, director of the Alzheimer Disease Research Unit, McGill Center for Studies in Aging, Montreal, Canada, commented in the same release that hydromethylthionine is "the best hope we have right now for a disease-modifying drug acting on the tau pathology" associated with AD.

Heather Snyder, PhD, vice president of medical and scientific relations for the Alzheimer's Association, told Medscape Medical News that the organization "looks forward to learning the results of the ongoing placebo-controlled trial in people living with mild to moderate Alzheimer's."

The study was sponsored by TauRx Therapeutics. Several authors are employees of the company and/or have financial relationships with the company.

J Alz Dis. Published online November 26, 2019. Full text

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